Decreased Expression and Androgen Regulation of the Tumor Suppressor Gene INPP4B in Prostate Cancer

Hodgson, Myles C.; Shao, Long Jiang; Frolov, Anna; Li, Rile; Peterson, Leif E.; Ayala, Gustavo; Ittmann, Michael; Weigel, Nancy L.; Agoulnik, Irina U.

doi:10.1158/0008-5472.can-10-2314

Cited by 127 publications

(191 citation statements)

References 55 publications

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“…70 Recently, INPP4B, a 4′ phosphoinositide phosphatase that specifically dephosphorylates PI-3,4-P2, and by this further inhibits Akt, has been described as a tumor suppressor in breast and prostate cancers. [71][72][73] It would be worth investigating whether SHIP-2 or INPP4B inactivation coexists with PTEN loss in a subset of these tumors, leading to higher Akt activation and thus to another convergent mechanism of PI3K-Akt activation.…”

Section: Pten Loss and Intrapathway Additive Activationmentioning

confidence: 99%

PTEN Tumor Suppressor Network in PI3K-Akt Pathway Control

2010

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The PI3K-Akt pathway is a major survival pathway activated in cancer. Efforts to develop targeted therapies have not been fully successful, mainly because of extensive internal intrapathway or external interpathway negative feedback loops or because of networking between pathway suppressors. The PTEN tumor suppressor is the major brake of the pathway and a common target for inactivation in somatic cancers. This review will highlight the networking of PTEN with other inhibitors of the pathway, relevant to cancer progression. PTEN constitutes the main node of the inhibitory network, and a series of convergences at different levels in the PI3K-Akt pathway, starting from those with growth factor receptors, will be described. As PTEN exerts enzymatic activity as a phosphatidylinositol-3,4,5-trisphosphate (PIP 3 ) phosphatase, thus opposing the activity of PI3K, the concerted actions to increase the availability of PIP 3 in cancer cells, relying either on other phosphoinositide enzymes or on the intrinsic regulation of PTEN activity by other molecules, will be discussed. In particular, the synergy between PTEN and the circle of its direct interacting proteins will be brought forth in an attempt to understand both the activation of the PI3K-Akt pathway and the connections with other parallel oncogenic pathways. The understanding of the interplay between the modulators of the PI3K-Akt pathway in cancer should eventually lead to the design of therapeutic approaches with increased efficacy in the clinic.

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Section: Pten Loss and Intrapathway Additive Activationmentioning

confidence: 99%

PTEN Tumor Suppressor Network in PI3K-Akt Pathway Control

2010

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“…For example, in estrogen receptor (ER) þ breast cancers, activating mutations in the catalytic subunit of PI3Ka are common, whereas mutations in AKT1 and PTEN occur at lower frequency (3). In prostate cancer, loss of phosphatases including PTEN and INPP4B are common (4)(5)(6). In contrast to the RAF-MEK-ERK pathway, signaling through the PI3K/AKT/mTOR signaling network is noncanonical; the presence of mutations in multiple signaling components in tumor types such as endometrial (7) and bladder (8) supports this concept.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity, and Correlation of Monotherapy Activity with Genetic Background

Davies

Greenwood

Dudley

et al. 2012

Molecular Cancer Therapeutics

373

345

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AKT is a key node in the most frequently deregulated signaling network in human cancer. AZD5363, a novel pyrrolopyrimidine-derived compound, inhibited all AKT isoforms with a potency of 10 nmol/L or less and inhibited phosphorylation of AKT substrates in cells with a potency of approximately 0.3 to 0.8 mmol/L. AZD5363 monotherapy inhibited the proliferation of 41 of 182 solid and hematologic tumor cell lines with a potency of 3 mmol/L or less. Cell lines derived from breast cancers showed the highest frequency of sensitivity. There was a significant relationship between the presence of PIK3CA and/or PTEN mutations and sensitivity to AZD5363 and between RAS mutations and resistance. Oral dosing of AZD5363 to nude mice caused doseand time-dependent reduction of PRAS40, GSK3b, and S6 phosphorylation in BT474c xenografts (PRAS40 phosphorylation EC 50 $ 0.1 mmol/L total plasma exposure), reversible increases in blood glucose concentrations, and dose-dependent decreases in 2[18F]fluoro-2-deoxy-D-glucose ( 18 F-FDG) uptake in U87-MG xenografts. Chronic oral dosing of AZD5363 caused dose-dependent growth inhibition of xenografts derived from various tumor types, including HER2þ breast cancer models that are resistant to trastuzumab. AZD5363 also significantly enhanced the antitumor activity of docetaxel, lapatinib, and trastuzumab in breast cancer xenografts. It is concluded that AZD5363 is a potent inhibitor of AKT with pharmacodynamic activity in vivo, has potential to treat a range of solid and hematologic tumors as monotherapy or a combinatorial agent, and has potential for personalized medicine based on the genetic status of PIK3CA, PTEN, and RAS. AZD5363 is currently in phase I clinical trials. Mol Cancer Ther; 11(4); 873-87. Ó2012 AACR.

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“…6 It is reported that INPP4B is highly expressed in prostate intermediate cells 7 but decreased in PCa tissues. 6 Cumulative evidences have demonstrated that loss of INPP4B expression correlates with disease recurrence and poor clinical outcome for PCa patients. 7 Moreover, INPP4B was proved to be an androgen responsive gene, 6 and overexpression of INPP4B contributes to an antitumor effect in therapy for CRPC.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-590-3p promotes cell proliferation and invasion by targeting inositol polyphosphate 4-phosphatase type II in human prostate cancer cells

Chen

Luo

2017

Tumour Biol.

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Inositol polyphosphate 4-phosphatase type II emerges as a tumor suppressor in prostate cancer, and its loss of expression is associated with poor prognosis for prostate cancer. However, the mechanism of downregulation of inositol polyphosphate 4-phosphatase type II in prostate cancer development has not yet been fully clarified. In this study, microRNA-590-3p was found to be upregulated in both prostate cancer tissues and cell lines. Overexpression of microRNA-590-3p by microRNA-590-3p mimics promoted prostate cancer cell proliferation and invasion and accelerated the growth of xenografted tumors, while microRNA-590-3p inhibitors contributed to inhibition of cellular proliferation and invasion as well as tumor growth. A dual-luciferase reporter assay and expression analysis further confirmed that inositol polyphosphate 4-phosphatase type II was a direct target of microRNA-590-3p. Enforced expression of microRNA-590-3p led to repression of inositol polyphosphate 4-phosphatase type II messenger RNA and protein expression, as well as upregulation of p-Akt, p-FoxO3a, and cyclin D1 and downregulation of p21 expression in prostate cancer cell lines. Overexpression of inositol polyphosphate 4-phosphatase type II could reduce microRNA-590-3p-induced cell proliferation and invasion as well as tumor growth, and decrease microRNA-590-3p-mediated upregulation of cyclin D1 and downregulation of p21 expression in prostate cancer cells. Taken together, our findings reveal that microRNA-590-3p is a potential onco-microRNA that participates in carcinogenesis of human prostate cancer by suppressing inositol polyphosphate 4-phosphatase type II expression and involving the Akt/FoxO3a pathway. MicroRNA-590-3p may represent a potential therapeutic target for prostate cancer patients.

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Decreased Expression and Androgen Regulation of the Tumor Suppressor Gene INPP4B in Prostate Cancer

Cited by 127 publications

References 55 publications

PTEN Tumor Suppressor Network in PI3K-Akt Pathway Control

PTEN Tumor Suppressor Network in PI3K-Akt Pathway Control

Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity, and Correlation of Monotherapy Activity with Genetic Background

MicroRNA-590-3p promotes cell proliferation and invasion by targeting inositol polyphosphate 4-phosphatase type II in human prostate cancer cells

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